Summary: New research from the University of Alabama at Birmingham shows that adult neurogenesis in the dentate gyrus not only adds new neurons to hippocampal circuits but also redistributes synaptic connections from older, mature neurons to those newly born cells. The study also uncovers a role for the Bax gene in synaptic pruning within this circuit.
Source: University of Alabama at Birmingham
Understanding how electrical signals flowing through brain circuits produce perception, action, learning and memory is a central aim of neurobiology.
Linda Overstreet-Wadiche, Ph.D., and Jacques Wadiche, Ph.D., associate professors in the Department of Neurobiology at the University of Alabama at Birmingham (UAB), led a study focused on the dentate gyrus, a subregion of the hippocampus crucial for forming distinct memories. The dentate gyrus is one of only two brain regions where new neurons continue to be produced throughout adulthood. These adult-born granule cells must form synaptic connections—“get wired in”—to participate in circuit function.
The dentate granule cells receive input from the entorhinal cortex, which integrates sensory and spatial information from other brain regions. By combining these streams of input, the dentate gyrus helps create unique memory representations for experiences. Because neurogenesis increases neuron number in the dentate gyrus while cortical neuron numbers remain stable, Overstreet-Wadiche and colleagues asked a basic but critical question: when new granule cells integrate, do entorhinal cortical neurons form additional synapses to contact both old and new granule cells, or do some cortical neurons shift connections away from mature granule cells and onto the newly born ones?
The investigators addressed this question using a combination of electrophysiology, dendritic spine density analysis and immunohistochemistry in genetically modified mice. The mouse models were designed either to increase the number of new neurons or to eliminate newborn cells. Their results support the latter scenario: new granule neurons acquire connections in part by drawing synapses away from preexisting mature granule cells. In other words, some cortical inputs reassign their connections from older neurons to new neurons.
These findings indicate that adult neurogenesis contributes to network plasticity not only by adding neurons but also by reshaping existing synaptic relationships. “To win synaptic connections, new cells cause older cells to lose connections,” the team reports, demonstrating a competitive redistribution process in the dentate circuit. This redistribution raises important functional questions: does the reassignment of synapses disrupt previously stored memories, or does it support improved encoding of new information? How do known neurogenic stimuli such as exercise—an established enhancer of adult neurogenesis—affect this synaptic competition and the resulting memory dynamics?
In addition to demonstrating synaptic redistribution, the researchers discovered an unexpected role for the pro-apoptotic gene Bax in synaptic pruning. Bax is conventionally associated with programmed cell death, but the new data indicate that Bax signaling also influences the strength and number of synaptic connections within the dentate gyrus. The work suggests that the same cellular machinery that governs cell survival and death may participate in ongoing synaptic refinement.
Maintaining a balanced pattern of synaptic strengthening and weakening—collectively termed synaptic plasticity—is essential for healthy brain function. Disrupted pruning or inappropriate synapse loss has been implicated in neurodevelopmental and neurodegenerative disorders. Understanding molecular contributors like Bax that influence pruning could therefore provide insight into conditions where synaptic organization is altered.
All experiments were conducted in the UAB Department of Neurobiology. The published paper, titled “Adult born neurons modify excitatory synaptic transmission to existing neurons,” appears in eLife. Lead authors include Elena W. Adlaf (whose doctoral thesis provided much of the data), Ryan J. Vaden, Anastasia J. Niver, Allison F. Manuel, Vincent C. Onyilo, Matheus T. Araujo, Cristina V. Dieni, Hai T. Vo and Gwendalyn D. King, with Jacques I. Wadiche and Linda Overstreet-Wadiche as senior authors.
Key findings summarized:
- Adult neurogenesis alters excitatory synaptic transmission onto mature dentate neurons, consistent with redistribution of preexisting synapses toward newly integrating neurons.
- Increasing neurogenesis by conditional deletion of Bax in neural stem cells reduced excitatory postsynaptic currents (EPSCs) and spine density in mature neurons.
- Genetic ablation of neurogenesis resulted in increased EPSCs in mature neurons.
- Surprisingly, deletion of Bax in developing and mature dentate neurons increased EPSCs and prevented neurogenesis-induced synaptic suppression, indicating a non-apoptotic role for Bax in synaptic refinement.
Funding: This research was supported by Civitan International Emerging Scholars awards and grants from the National Institutes of Health (NS098553, NS064025, NS065920, NS047466).
Original research: “Adult-born neurons modify excitatory synaptic transmission to existing neurons.” Elena W. Adlaf et al., eLife. Published online January 30, 2017. DOI: 10.7554/eLife.19886
The study advances our understanding of how adult-born neurons influence existing circuits: by both adding cellular elements and actively reshaping synaptic connectivity. These dual effects of neurogenesis—cell addition and circuit remodeling—may help explain why increased neurogenesis can enhance learning of new information, while also being implicated in the forgetting or modification of old memories. Future work will be needed to define how synaptic redistribution affects behavior and to clarify how physiological regulators of neurogenesis, such as exercise, interact with molecular players like Bax to sculpt hippocampal circuits.